The Akt/mTOR pathway is an emerging target in cancer, because Akt and mTOR are constitutively active in many types of cancer, which often confers a poor prognosis. Our studies have identified an important role for this pathway in the formation, maintenance, and therapeutic resistance of lung cancer. Although no defined Akt inhibitors are currently available for clinical testing, other inhibitors of the PI3K/Akt/mTOR pathway are avialable for clinical testing. We have a series of therapeutic and non-therapeutic protocols that are currently open, as well as protocols that are in the planning stage. Our therapeutic protocols utilize pathway inhibitors as single agents or in combination with other standard chemotherapies, and our protocols are open at the Clinical Research Center as well as at the National Naval Medical Center. Currently, there is a Phase I trial of nelfinavir in subjects with relapsed for refractory solid tumors that is open at the Clinical Research Center and NCI/Navy Medical Oncology. This protocol is based on our preclinical studies that showed that nelfinavir is an effective anti-cancer agent in vitro and in vivo that works through multiple mechanisms including Akt inhibition and the induction of apoptosis, ER stress and autophagy. A second protocol that is open is a Phase I/II protocol of combining sirolimus (an inhibitor of mTOR) with pemetrexed in patients with refractory or resistant NSCLC. This protocol is based on work from our laboratory that shows that this combination was highly effective in vitro and in vivo. A third protocol that is open is a pilot trial of sirolimus in patients with PTEN hamartoma tumor syndromes (PHTS). The most common syndrome in PHTS is Cowden Syndrome, and all of these syndromes are characterized by benign tumors in many tissues and an increased predisposition to many types of cancer. Because most of these patients have germline mutations in the tumor suppressor PTEN, which negatively controls the Akt/mTOR pathway, we are testing whether sirolimus will inhibit mTOR in various tissues, and whether it will affect tumor growth or metabolism. The last trial that is open is a tissue procurement study at NCI/Navy Medical Oncology. This protocol allows to procure tissues from cancer patients when it does not involve significant morbidity. Such tissues are anonymized and are quite valuable in studies designed to assess new predictive or prognostic biomarkers. Finally, we have other trials that are in the approval process but are not yet open. These include a pilot prevention study of sirolimus in heavy smokers or those at high risk to develop lung cancer, a trial of the Akt inhibitor (triciribine) in combination with erlotinib (an FDA approved inhibitor of the epidermal growth factor receptor), and a natural history study of lung cancer or those at high risk who are active duty military. These studies are consistent with our mission and will further our understanding of the utility of inhibiting the Akt/mTOR pathway for the treatment or prevention of lung cancer.